Question

A review on preclinical studies of a CNS drug approved in the last 5 years in 1000 word.

Answer 1

The failure rate for new drugs targeting important central nervous system (CNS) diseases is very high relative to most other areas of drug discovery, a fact reflected in the many pharmaceutical company CNS programs that have been disbanded or significantly reduced. This is most apparent in the case of drugs that attempt to alter the course of the disease or condition (disease modifying drugs), and is particularly acute in the area of neurodegenerative diseases (NDDs). In many cases, the drugs that have had demonstrable effects are palliative treatments that have modest effects on disease symptoms and no demonstrable effect on disease progression.

For any disease, it is difficult to discover effective and safe drugs. Discovering and developing a successful drug depends on very detailed knowledge of underlying disease mechanisms and a successful progression from candidate identification to clinical trial design. The pharmaceutical industry (for all the right reasons) is heavily regulated, and it is one of the few industries where, despite the investment of a great deal of capital and time, the majority of efforts result in complete failure. While other industries, such as the aircraft industry, are equally regulated at a certain level, the result of that scrutiny is rarely a completely unusable aircraft, or the irreversible denial of marketing approval for a new airplane. We understand enough about the physics of flight to assure that planes will fly, and an iterative process with regulators makes sure they fly safely. In the discovery and development of new medicines, this is not a certainty: we do not have any a priori reason to expect that we can intervene with pharmaceutical agents in any disease, and it is never assured that a drug will be approved for marketing.

Almost miraculously, in many types of disease, such efforts have been very successful, although in very few instances can pharmaceutical treatments be considered cures. Some disease areas, frankly, have proven more tractable than others, and almost all other areas are easier than targeting many types of CNS disease. For example, anti-infective agents target organisms that are foreign invaders in our particular internal ecosystems, presenting almost unlimited opportunity for novel and effective agents to kill pathogens while sparing our own cells. The rapid progress in discovering and developing life-saving medicines in areas such as HIV-AIDS and other viral disease demonstrates that when there is sufficient cooperation between the relevant government agencies, academia and the pharmaceutical/biotech industry, and pressure from patient advocates, progress in such diseases can be very rapid and effective.The same will likely be true with antibiotic resistance and parasitic diseases in the near future, it will just require the political will to do it on a grander scale, and new models for recouping investments for short-term treatments or treatments aimed at third-world patient cohorts. While these types of collaborative efforts have also paid off well in other areas such as cancer and heart disease, thus far they have not led to effective treatments in many of the major CNS disorders. They have begun, however, and there is every reason to be optimistic.

In all disease areas, there are several common requirements for designing and implementing a successful effort to discover new treatments. The natural history of the disease or condition must be well understood. A potential molecular target has to be identified, and a testable hypothesis must be generated concerning the role of the new molecular target in either the generation or amelioration of the disease state or condition. A model of the disease must be created that is believed to have predictive validity for use in preclinical tests and that involves induction of the disease, or a mechanistically-related disease, in animals or in vitro. A directed program must be initiated to generate molecules to test. If a candidate molecule is identified that fulfills a number of pre-clinical criteria such as dose-dependent efficacy in the model(s), metabolic stability and a sufficient degree of animal safety at multiples of presumed therapeutic doses, a drug candidate may be taken into carefully designed and tightly regulated clinical trials to determine its safety and efficacy. Initially the safety of the drug candidate is tested in healthy human subjects, and eventually in human subjects with the disease. If efficacy is demonstrated that is greater, in the context of the particular disease, than the risks associated with the drug it may be approvable and eventually marketed and made available to patients.

These above steps have been followed in the development of drugs that act on the CNS, but levels of clinical failures are higher than in other therapeutic target areas, most often because of lack of any significant evidence of clinical efficacy. While drugs often fail prior to understanding whether they are efficacious, it is failure for lack of efficacy that is most vexing, expensive and leads to the greatest likelihood of retreat from a disease target. This occurs repeatedly despite seemingly adequate and appropriate preclinical data demonstrating that candidates should work well, and have seemingly adequate clinical safety margins. No one makes the decision to advance a drug into very expensive and time-consuming clinical trials lightly. While there have been some obvious mistakes, usually based on assumptions later proven wrong, the preclinical packages used to propel CNS drugs into the clinic are just as convincing and well-executed as those for any other therapeutic area. Clearly, there is a major disconnect, at least in some CNS sub-disciplines. Post hoc analyses may point to specific aspects of a clinical trial that may have contributed to the lack of a positive signal, and such analyses are useful and necessary. Failures due to lack of efficacy, however indicate that there may be serious flaws in the hypothesis. As a result, negative results may be critical to understanding how to make successful drugs. Negative results should therefore be published, but often have not been.

There have been decades of significant advances in our knowledge regarding the basic neurosciences, including neuropharmacology, yet treatment of symptoms rather than cause characterizes most CNS pharmaceutical approaches. For example, most treatments for pain reduce sensation, but do not durably affect the cause of the aberrant sensation. In acute pain, this is acceptable, because the cause is self-limiting due to healing, but in chronic and neuropathic pain when the medication is removed, the pain returns. In psychiatric disorders treatment of symptoms can be very effective, even if accompanied by serious side effects, but again, if medication is terminated, the disease symptoms almost always recur without diminution. Thus, in the absence of other treatments, such drugs have to be taken for life. In both areas, the fact that drugs treat symptoms but do not affect the disease process would be fine if the drugs had few if any side effects impacting quality of life or drug compliance, had no abuse potential, did not often induce tachyphylaxis or other forms of drug resistance, and were not economically challenging to individuals or healthcare systems. Of course, all of those issues do apply to one degree or others

The worst outcomes (in those areas where programs have been attempted) are seen in the major chronic NDDs, including Parkinson’s disease (PD), Alzheimer’s disease (AD) and neuromuscular disorders, including amyotrophic lateral sclerosis . In these disorders the widespread degeneration (death) of neurons (AD) or the more focused death of specific populations of central cells (PD and ALS) leads to increasing dysfunction in individuals, and eventually death. Currently, all of the approved treatments for these diseases are palliative. Symptomatic treatments for these chronic NDDs have been approved: these include dopaminergic modulators for PD

Even at the preclinical stage, it is more difficult to make findings in CNS disease that can be translated into a successful clinical candidate than in most other areas. The brain is a protected compartment (the blood-brain barrier, or BBB) (Begley, 2004; Oby and Janigro, 2006; Pardridge, 2012), and entry of molecules into the CNS is limited and requires special attention by medicinal chemists and whole-animal pharmacologists. Many of the techniques commonly used to increase brain penetration by small molecules, such as increasing lipophilicity, can dramatically reduce solubility, leading to difficulties in drug delivery. Many classes of large molecules, such as peptides and antibodies, will not readily access the CNS without some form of assisted transport (see elsewhere in this issue). Nevertheless, of all the reasons for clinical CNS drug failure, this is the least important historically, and rarely resulted in clinical failure. With few exceptions, drugs are not taken into clinical trials if some mechanism for CNS entry cannot be demonstrated, and sufficient brain levels are not reached in animal models. In our further discussion of why CNS drug programs fail, we will assume that the failed drugs passed all preclinical requirements to enter the clinic.

Certain factors can cause clinical drug failures in any disease area, and CNS is no exception. These include an unacceptable pharmacokinetic (PK) profile in humans. While many preclinical models of PK exist with reasonable predictive validity, unexpected metabolic differences can arise and cause the withdrawal of a drug candidate. Usually, this will be detected early in development, unless the final phase of development involves a population of subjects that have not historically been included in safety assessments in healthy volunteers or initial assessments in subjects with the disease. Such populations include women, the aged or chronically ill, and, particularly in the case of women, this factor has resulted in changes in research and clinical trials industry-wide.

Another factor common across disease areas is the problem of both predicted and emergent toxicity. All drugs are assessed for safety, and the yardstick for deciding if a toxicity profile is acceptable will involve a careful and ongoing assessment of the risk/benefit ratio. The levels of acceptable risk are greater in diseases where the untreated outcome is dire and no effective standard-of-care treatment exists. This is particularly true when a drug regimen is time-limited, and the subject is able to recover and enjoy relief from disease following cessation of treatment. Many oncologic treatments, even the most recent immunotherapies, can be highly toxic, but if successful the disease is in remission and treatment is concluded, at least for a time. Deaths attributable to treatment may even be noted, but a drug may be approved if the population benefit outweighs the individual risk. Because the CNS determines every aspect of our personality and controls all behavior, side-effects, even if not reflecting toxicity in the usual sense, can end the development of a drug if they cause significant neurologic or behavioral dysfunction, or if patients will not take them.

Sometimes incomplete knowledge of the natural history of a disease, coupled with the fear of side effects and even commercial concerns about reimbursement, can contribute to clinical failure that otherwise may have resulted in success. In the area of ischemic stroke evidence has accumulated that the area of impacted brain continues to increase long after the 3–4 days post insult that had originally been postulated